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1、1 ADC药物偶联技术的发展药物偶联技术的发展 及相关质量研究及相关质量研究 李壮林李壮林 烟台荣昌生物工程有限公司 August 13, 2014 Global top 10 drugs in 2013 2 临床上单独使用单克隆抗体的抗肿瘤的作用有限。如何增强单克隆抗临床上单独使用单克隆抗体的抗肿瘤的作用有限。如何增强单克隆抗 体的抗肿瘤的作用？那就是在抗体上挂上一个炸弹或称细胞毒素。体的抗肿瘤的作用？那就是在抗体上挂上一个炸弹或称细胞毒素。 3 ADC （Antibody Drug Conjugate） 5 ADC Drugs: A Novel Class of Targeted Bio-
2、Therapeutics Current Cancer Drug Targets, 2009, 9, 982-1004 B.A. Teicher Antibody-drug conjugate targets 6 Current Cancer Drug Targets, 2009, 9, 982-1004 B.A. Teicher, Antibody-drug conjugate targets 7 ADC DesignationsTarget Antigen Linker-Drug Class DevelopmentTumor Indication(s)Developer SNG-35(Ad
3、cetris) SNG-75 Anti-CD19 ADC CD30 CD70 CD19 Auristatin Auristatin Auristatin Approved Phase/b NHL RCC/NHL Seattle Genetics Trastuzumab-DM1 Anti-CD22 ADC Her2 CD22 Maytansine Auristatin Approved Phase HER2+ Breast Ca Gastric Ca ALL Genentech AGS-5 ADC AGS-22M6E AGS-16M8F SLC44A4 Nectin-4 AGS-16 Auris
4、tatin Auristatin Auristatin Phase Phase Phase Pancreatic, Gastric Ca Solid Tumors Kidney, RCC(active, not recruiting) Astellas PSMA-ADCPSMAAuristatinPhase/ProstateProgenics BIIB015Anti-CriptoAuristatinPhaseSolid TumorBiogen Idec CDX-011GPNMBAuristatinPhase/Breast, MelanomaCelldex BAY79-4620 Carbonic
5、 anhydrase9 AuristatinPhase Solid Tumor (active, not recruiting/terminated) Bayer BAY94-9343mesothelinMaytansinePhaseSolid TumorBayer SAR3419 SAR566658 AVE9633 CD19 CA6 CD33 Maytansine Maytansine Maytansine Phase/ Phase Phase ALL, NHL, B cell lymphoma Malignant neoplasm(solid) AML(terminated) Sanofi
6、 BT-062CD138MaytansinePhase/Multiple Myeloma (MM)Biotest IMGN242 IMGN901 IMGN388 IMGN368 CanAng CD56 Av Integrin Av Integrin Maytansine Maytansine Maytansine Maytansine Phase Phase/ Phase Solid Tumor MM, Lung Ca, Ovarian, SCLC Solid Tumor ImmunoGen CMC-544CD22CalicheamicinPhaseb/NHL, ALL,B cell lymp
7、homaPfizer MDX1203CD70DuocarmycinPhase RCC/NHL(suspended)BMS ADC Drugs under clinical development 8 9 ADC Drugs Approved by USA FDA Drug name mAb(Antigen)Drug/Linker Drugs/Ab (average) Conjugate Chemistry ReducableTriggerStatus Mylotarg Gemtuzumab ozogamicin (CD-33) Calicheamicin /Hydrazone 4-6(5*)L
8、ysineYespH approved (2000) withdraw (2010) Adcetris Brentuximab vedotin (CD-30) Monomethyl aurisatin E(MMAE)/ MC-VC-PAB 3-5(4)CysteineNoprotease approved (2011) at phase Kadcyla Trastuzumab emtansine (Her-2) Mertansine(D M1)/SMCC 0-8(3.5)LysineNonone approved (2013) accelerated 10 Four Lessons learn
9、ed from Mylotarg Dosio et al, Toxins, 2011, 3:848 Only 50% Amb conjugated drugs Hydrazone bond not stable in blood Disulfide bonds premature broken Shed Calicheamicin can penetrate cells 11 Carbohydrate Thiobridge Thiophenol Non-natured Amino acids Cysteine Lysine Conjugation Technologies NH2 NH2 NH
10、2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 SH SH SH SH Lysine Conjugate vs. Cysteine Conjugate 代表Lys，氨基偶联为主 代表Cys，巯基偶联为主 定点偶联为主 12 13 Lysine Conjugation # drug / mAb molecule 14 Genentechs anti-Her2 ADC drug T-DM1 (Kadcyla) 15 Structure of trastuzumab (Tmab)maytansinoid co
11、njugates (stability of linker, least to greatest): Tmab-SPDP-DM1, Tmab-SPP-DM1, Tmab-SSNPP-DM3, Tmab-SSNPP-DM4, and Tmab-SMCC-DM1 T-DM1 linker evaluation Gail D. Lewis Phillips, Cancer Res 2008; 68: (22). 16 T-DM1 linker evaluation Gail D. Lewis Phillips, Cancer Res 2008; 68: (22). 17 Herceptin VS T
12、-DM1 Gail D. Lewis Phillips, Cancer Res 2008; 68: (22). 18 Drug Distribution of Cysteine Conjugation # drug / mAb molecule Reduced or broken disulfide bonds for drug conjugation lead to antibody unstable with a shorter half life-challenge solution. 19 Seattle Genetics anti-CD-30 ADC drug SGN-35 (Bre
13、ntuximab vedotin) 20 SGN-35 (Brentuximab vedotin) 临床试验临床试验 - SGN-35在Hodgkin lymphoma (HL)表现出非常好的抗肿瘤活性; - SGN-35在Systemic anaplastic large cell lymphoma (ALCL)也呈现显著的抗肿瘤活性; - 2011年8月，FDA根据II期临床试验结果批准SGN-35用于HL治疗， 后又批准用于 ALCL治疗。 RCBiotech LTD Andrew C.Huang Ph.D. 2014 05 Seattle Genetics Inc. 完成完成7个临床实
14、验表明个临床实验表明Adcetris安全有效安全有效 21 22 Site-specific Conjugation # drug / mAb molecule 23 Site-specific Conjugation Axup et al， 24 Site-specific Conjugation Axup et al， HIC-HPLC Analysis on ADC drug with Cysteine Conjugation Aditya Wakankar et al, mAbs,2011,3:2, 161-172 25 (AD) DTT-reduced cAC10-vcMMAE co
15、njugates produced using different reduction/reoxidation protocols. (EH) Analysis of the same conjugate samples in (AD), under non-reducing conditions, Aditya Wakankar et al, mAbs,2011,3:2, 161-172 26 Reversed-phase HPLC analysis 27 Conjugation site analysis in T-DM1(Enzymatic cleavage ) by RP-HPLC E
16、nzymatic cleavage of ADCs can be used to identify drug-containing peptides. Peptides labeled with a hydrophobic drug would be expected to elute later than their unmodified forms in the RP-HPLC chromatogram due to increased retention by the column. Trastuzumab has 88 lysines for possible linkage. DM1 chromophore ( max=252nm) can be used to iden
